This Competitive Revision is submitted in response to NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". In this Competitive Revision, we will accelerate the tempo of funded experiments by adding personnel. In addition, we will also expand the scope of the original proposal to include additional experiments that will enhance the pre-clinical/translational studies in this proposal. The objective of this funded grant is to use genetic and pharmacologic strategies to validate the EP4 receptor as an appropriate therapeutic target in the APPSwe-PS1(9 model of Familial Alzheimer's disease. An expansion of our experimental goals has been prompted by our discovery of anti- inflammatory and neuroprotective effects of EP4 signaling in brain. In the first set of additional experiments we will refine our genetic characterization and identify the cellular mechanism of EP4 action in aging APPS mice. In a second series of new experiments, we will determine changes in secreted plasma protein levels arising as a result of genetic or pharmacological manipulation of EP4 signaling in aging APPS mice. These new experiments are appropriate in the context of this pre-clinical/translational R21 because they provide mechanistic insight into the cellular basis of EP4 signaling in this model of AD that will enhance future pre-clinical development. Alzheimer's disease (AD) is characterized by a dominant component of inflammation, which in concert with enhanced amyloid production leads to secondary neuronal degeneration. Additionally, recent evidence also suggests a strong link between cerebrovascular disease and development of dementia in AD. Thus, the combined anti-inflammatory and neuroprotective effects of EP4 signaling in brain makes it a very attractive therapeutic target for models of AD, in which there are components of both inflammation and neurotoxicity. Successful target validation of the EP4 receptor will provide the rationale for future and expanded pre-clinical assessment of agonists of this receptor in AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is characterized by a dominant component of inflammation, which in concert with increased amyloid production leads to neuronal injury and loss. The goal of the present proposal is to validate the PGE2 EP4 receptor as a therapeutic target in the prevention and/or treatment of AD. Successful target validation of the EP4 receptor will provide the rationale for future and expanded pre-clinical assessment of agonists of this receptor in AD.